Identifying the Genetic Cause of Congenital Heart Dfects using Exome Analysis

Background: Congenital heart defects (CHD) incidence is ~1% of live birth and are a major cause of neonatal and infantile morbidity and mortality. CHD can be part of a syndrome with known genetic background, though the diagnostic genetic test is not always available to the family. In some cases, consanguineous marriage and multiple affected siblings in the same family raise the possibility of autosomal recessive inheritance, yet the challenge of identifying the exact disease-causing mutation is significant. In both scenarios, exact genetic diagnosis allows for genetic counseling and open the way for pre-marital, preimplentation or prenatal diagnosis, hopefully enabling prevention of CHD.

Methods: Using exome analysis in two groups of patient:

Group A: 9 patients with clinical diagnosis of a CHD as part of a known syndrome; 7 with Noonan syndrome and 2 with Marfan syndrome.

Group B: 14 patients from families with consanguineous marriage and multiple affected siblings in the same family.

Results: In group A, a genetic diagnosis was made in 8/9 patients; 6/7 with Noonan syndrome and 2/2 with Marfan syndrome. In group B, a genetic diagnosis was made in 8/14 patients.

Discussion: In Noonan and Marfan syndromes there is a high rate of cardiac involvement with significant morbidity. Though the knowledge regarding the genetic basis of those syndromes has increased dramatically in the last 2 decades, there is still great need in improving the availability of a diagnostic genetic test to the affected families. In addition, there are cases where the detailed family history regarding the CHD points toward high probability of an autosomal recessive inheritance pattern. In these cases one should consider the use of exome analysis.

Conclusion: For selected patients suffering from CHD, exome analysis is an efficient and fast tool for determining the underlying disease-causing mutation.